Breast cancer is the most common noncutaneous cancer in North American women, with an estimated 192,000 newly diagnosed cases in 2001 in the United States alone. Breast cancer also appears in males although it is rare: about 1% of the incidence in women. In Connecticut, where longitudinal cancer statistics are available, breast cancer increased about 1% a year from the 1940s to 1980. Between 1982 and 1987, it increased about 4% a year, in association with the widespread use of screening by mammography (1-4).
Because of this high incidence, breast cancer is the second most common cause of cancer-related death in women in North America, with an estimate of over 40,000 cancer fatalities in 2001, i.e. approximately 25% of breast cancer cases end in death (1). Therefore, preventing the development of breast cancer, and death from it, is an extremely important task in North America and other populations where breast cancer rates are increasing rapidly. Because there are no realistic prospects of significantly improving the cure rate once the cancer has spread, many authorities believe that breast cancer can be effectively controlled only by preventive measures, as it has been documented for colorectal cancer (5).
Primary prevention of breast cancer (i.e. averting the development of the tumor by altering biological risk factors) is not yet feasible since so little is understood of the etiology of the disease. Alternatively, secondary preventive measures (i.e. detection at an asymptomatic, treatable state) would be possible should an effective screening test be available. Indeed, breast cancer has the characteristics of a suitable candidate for the development of a screening test: (1) it is a common cause of cancer-related deaths and the disease prevalence is sufficiently high to justify the expense of a screening program; (2) once the stage of invasive cancer is reached, leading to symptoms, the mortality rate is over 25%; and (3) removal of breast cancer at its earliest, asymptomatic stage can be done by limited surgical intervention, without any significant risk. Moreover, as breast cancer may become metastatic and increasingly fatal in a short time, the opportunity to detect these neoplasms at their treatable stage is limited. Therefore a screening test which would enable early diagnosis of the disease is of utmost importance.
Principles of Screening
The goal of a medical screening program is to reduce mortality by detecting a disease at a sufficiently early stage to allow curative treatment. Usually it is not designed to diagnose a disease, but to determine which asymptomatic, apparently disease-free individuals should undergo diagnostic investigations. The effectiveness of a screening test to distinguish those who warrant further evaluation from those who do not is expressed in the following epidemiological terms: sensitivity, specificity, positive predictive value, and negative predictive value. Sensitivity is defined as the proportion of diseased individuals who have a positive test (true positives/all persons with the disease); specificity is the proportion of disease-free subjects who have a negative test (true negatives/all persons without the disease; positive predictive value is the proportion of positive tests due to the disease (true positives/all positives); negative predictive value is the proportion of negative tests due to the absence of the disease (true negatives/all negatives). Almost always, sensitivity and specificity must be traded against each other. Intuitively, it appears wise to design a screening test for a fatal disease so as to optimize sensitivity, in order to detect as many individuals with the disease as possible. It has been emphasized, however, that optimizing sensitivity brings with it a risk of reducing the specificity to such an extent that unacceptably high costs, poor compliance, and “flooding” of diagnostic facilities result. Moreover, positive predictive value which is a particularly useful expression of the value of screening test is critically dependent on specificity and on how common the occurrence of a disease is in the population screened (6).
Screening Using a Schiff's Reagent
Colorectal mucus from patients with colorectal cancer turns purple on treatment with Schiff's reagent as disclosed in U.S. Pat. No. 5,416,025 to Krepinsky et al. More specifically, in U.S. Pat. No. 6,187,591 to Krepinsky et al. it is documented that the aldehydes selected from the group consisting of the following aldehydes that are insoluble in water: hexadecanal CH3(CH2)14CH══O commonly known as palmitaldehyde, octadecanal CH3(CH2)16CH══O commonly known as stearaldehyde, and octadec-9-enal, CH3(CH2)7CH══CH(CH2)7CH══O, commonly known as olealdehyde, provide markers of cancer in colorectal mucus obtained by digital rectal examination in colorectal cancer patients (U.S. Pat. No. 5,416,025 to Krepinsky et al., U.S. Pat. No. 6,187,591 to Krepinsky et al, and 7).
Current Modalities of Breast Cancer Diagnosis and Screening
Breast Self Examination (BSE)
Monthly BSE is frequently advocated, but after many large scale studies have been conducted, there is no evidence for its effectiveness (8).
Clinical Breast Examination (CBE)
Clinical breast examination (by a health care practitioner) may discover breast cancers that are not detected by the patient or by other screening methods (4), but no randomized trials of CBE as a sole screening modality have been done. Based on studies that combined CBE with other modality, CBE may be effective with a sensitivity of 70% to 80%, and specificity of close to 90% (9).
Mammography
Mammography utilizes X-rays to identify differences in breast tissue density. The examination is performed by compressing the breast firmly between a plastic plate and a plate covering an x-ray cassette which contains special x-ray film. The density of cancer tissue is higher. This difference can be observed in conventional mammography directly on the film, or in digital mammography using computer-assisted evaluation to create breast tissue images. Mammography can identify breast cancers too small to be palpated on physical examination, and can also find ductal carcinoma in situ (DCIS), a noninvasive condition (10). Since all cancers develop as a consequence of a series of mutations, it is theoretically beneficial to diagnose these noninvasive lesions. However, whether mass screening with mammography ultimately saves lives is still a subject of heated debate. Most recently, a review published by Cochrane Library concluded that there is no evidence that mammography saves lives in the long run (11-13).
Ultrasonography
The primary role of ultrasound is the evaluation of palpable or mammographically identified masses. A review of the literature and expert opinion by the European Group for Breast Cancer Screening concluded, “there is little evidence to support the use of ultrasound in population breast cancer screening at any age” (14).
Magnetic Resonance Imaging (MRI)
MRIs have been used to evaluate palpable breast masses and to discriminate between cancer and scar, but their role in breast cancer screening has not been established (15).
DNA Analysis
Screening for breast cancer by DNA analysis is based on the presence of altered genes such as BRCA1 and BRCA2 in women with increased risk for the development of the disease (16). However, the majority of breast cancer cases (approximately 90%) are sporadic (17), i.e. no hereditary links could be identified, and therefore DNA analysis could not identify them.
Breast Secretion Fluids
It is believed that neoplastic changes occur in one breast duct at the onset of the disease and may involve other ducts as the disease progresses (20). Since cancer cells may slough off and enter into the ductal fluids, cytological examinations of fluids and identification of atypical cells has been considered as a tool to detect the presence of neoplasia and cancer. In particular, many investigations utilizing nipple aspirate fluid (18, 21-24) have been conducted and correlations of abnormal cytology of breast secretion fluids (19) with breast neoplasia and cancer have been reported (25-33). However, cytological analysis is laborious and requires relatively large volumes in order to obtain sufficient numbers of exfoliated cells, rendering this approach impractical for screening purposes.
In conclusion, there is a need for a simple screening test for breast cancer which may be used solely or in conjunction with other methods (such as clinical breast examination or mammography).